OVERALL PROJECT SUMMARY The impressive clinical successes in immune checkpoint inhibition (ICI) therapy over the last decade have not been matched by the development of clinically useful tools to predict patient response and toxicity. The integration of biomarkers of patient outcome and toxicity into clinical care would allow more optimal treatment selection. The primary objective of the New York University (NYU) Melanoma SPORE is to address the urgent need to develop and validate clinically useful, personalized biomarkers to optimally administer immune checkpoint inhibition therapies in the adjuvant setting. We have chosen to concentrate our efforts in this area because FDA approval of immunotherapies in this clinical context has led to a significant increase in the utilization of these treatments with expansion of adjuvant trials to other cancers. The use of adjuvant ICI will alter the immunobiology of melanoma and other malignancies as well. Identifying biomarkers of benefit and toxicity is critical, timely, and promises to have broad applicability. All of our projects were revised to reflect this adjusted focus, making the goals of the overall program more cohesive, achievable, and impactful. The development of new biomarkers requires a phased approach. The NYU Melanoma SPORE includes projects that span the biomarker development path from target identification and clinical relevance (Projects 1, 2, 3, 4), to assay and clinical validation (Projects 3, 4), and ultimately clinical utility with testing in an investigator-initiated clinical trial (Project 3). The NYU Melanoma SPORE is particularly well suited to achieve this objective due to our broad patient base and our translational expertise in biomarker identification and development. Physicians at NYU Langone Health (NYULH) treat over 1,000 new melanoma patients annually. As a flagship research program of the NCI-funded NYU Perlmutter Cancer Center (PCC), our melanoma translational research program has an established track record of collaboration and high impact findings in melanoma biomarker development, empowered by rich biospecimen resources from over 3,800 patients treated at NYULH These resources and extensive institutional infrastructure and capabilities will enable the NYU Melanoma SPORE to characterize novel personalized biomarkers for melanoma patient clinical management. The scope and scalability of these resources will extend to our studies of 2,700 melanoma patients enrolled in phase III, multisite clinical trials in the adjuvant setting (CheckMate 238, CheckMate 915 and KEYNOTE 716). The NYU Melanoma SPORE PD/PIs, Drs. Iman Osman and Jeffrey Weber, merge complementary expertise in melanoma ICI drug development, clinical trials, and biomarker investigations. We will apply our strengths to solve pressing needs in the melanoma field which which can be extended to the increasing number of ICI--treated cancers.